Abstract The Center for Disease Control reported that 7.8% of the US population suffered from asthma in 2015 with much higher incidences in those of African-American or Latino heritage (13.9%) or those below the poverty level (11.1%). For decades, asthma maintenance therapies have relied on inhaled corticosteroids and ?-agonists, yet nearly 40% of asthmatics have inadequate control of their symptoms. Emerging biologic therapies with antibodies targeting IgE, cytokines and cytokine receptors are limited to small subsets of carefully phenotyped patients, are expensive, and require monthly administration in a health care setting due to anaphylaxis potential. Moreover, no new therapeutic classes of medications that acutely relax airway smooth muscle and bronchoconstriction have been introduced for many decades. Novel therapies that target both airway smooth muscle relaxation and a reduction in allergic lung inflammation would be of enormous clinical benefit. We have identified purified natural components of ginger that acutely relax airway smooth muscle via inhibition of two families of phosphodiesterases that are critical importance in smooth muscle cell function; cyclic nucleotide phosphodiesterases (PDE) and phospholipase C (PLC). Since these compounds undergo metabolism, we have partnered with a world expert in 6-shogaol metabolism to identify human metabolites and even novel synthetic derivatives that retain enhanced potency for airway smooth muscle effects. We have also demonstrated dramatic anti-inflammatory effects of 6-shogaol and inhibition of phospholipase C signaling pathways in macrophages and lymphocytes. Thus, we present a unified cell signaling mechanistic hypothesis of how 6- shogaol derivatives achieve this dual benefit in allergic lung disease: relaxation of airway smooth muscle and anti-inflammation. In aim 1, we will continue our analysis of human metabolites and novel synthetic derivatives of 6-shogaol to identify the structural requirements for PLC and PDE inhibition and smooth muscle relaxation while identifying derivatives with greater potency than the parent 6-shogaol compound in human upper and lower airways. In aim 2, we will demonstrate the mechanism by that these novel metabolites and synthetic derivatives impair activation of human macrophages and CD4+ lymphocytes in vitro and in situ in murine precision cut lung slices. In aim 3, we will unite these mechanistic findings and demonstrate therapeutic potential in vivo. Acute bronchodilatory effects will be demonstrated by the forced oscillatory technique in mouse lungs and chronic anti- inflammatory effects during chronic house dust mite antigen sensitization will be demonstrated. These studies will demonstrate the function, mechanism and therapeutic potential of novel compounds with enhanced potency for targeting two key pathologic features of asthma; airway hyperresponsiveness and lung inflammation.